Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells

被引:4
|
作者
Okumura, Manabu [1 ,2 ]
Iwakiri, Tomomi [1 ]
Yoshikawa, Naoki [1 ]
Nagatomo, Takao [1 ]
Ayabe, Takanori [2 ,3 ]
Tsuneyoshi, Isao [2 ,4 ]
Ikeda, Ryuji [1 ]
机构
[1] Univ Miyazaki, Fac Med, Dept Pharm, Miyazaki 8891692, Japan
[2] Miyazaki Univ Hosp, Dept Patient Safety Management, Miyazaki 8891692, Japan
[3] Univ Miyazaki, Fac Med, Dept Surg, Div Thorac & Breast Surg, Miyazaki 8891692, Japan
[4] Univ Miyazaki, Fac Med, Dept Anesthesiol & Intens Care, Miyazaki 8891692, Japan
关键词
hepatocyte growth factor; HGF; 5-FU; UPP1; c-Met; erlotinib; RECEPTOR TYROSINE KINASE; C-MET; URIDINE PHOSPHORYLASE; OVEREXPRESSION; AMPLIFICATION; BINDING; CANCER; RILOTUMUMAB; SUPPRESSES; ACTIVATION;
D O I
10.3390/ijms23169108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
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页数:19
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